Coupling killing to neutralization: combined therapy with ceftriaxone/Pep19-2.5 counteracts sepsis in rabbits

Sepsis, which is induced by severe bacterial infections, is a major cause of death worldwide, and therapies combating the disease are urgently needed. Because many drugs have failed in clinical trials despite their efficacy in mouse models, the development of reliable animal models of sepsis is in great demand. Several studies have suggested that rabbits reflect sepsis-related symptoms more accurately than mice. In this study, we evaluated a rabbit model of acute sepsis caused by the intravenous inoculation of Salmonella enterica. The model reproduces numerous symptoms characteristic of human sepsis including hyperlactatemia, hyperglycemia, leukopenia, hypothermia and the hyperproduction of several pro-inflammatory cytokines. Hence, it was chosen to investigate the proposed ability of Pep19-2.5—an anti-endotoxic peptide with high affinity to lipopolysaccharide and lipoprotein—to attenuate sepsis-associated pathologies in combination with an antibiotic (ceftriaxone). We demonstrate that a combination of Pep19-2.5 and ceftriaxone administered intravenously to the rabbits (1) kills bacteria and eliminates bacteremia 30 min post challenge; (2) inhibits Toll-like receptor 4 agonists in serum 90 min post challenge; (3) reduces serum levels of pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α); and (4) reverts to hypothermia and gives rise to temperature values indistinguishable from basal levels 330 min post challenge. The two components of the combination displayed synergism in some of these activities, and Pep19-2.5 notably counteracted the endotoxin-inducing potential of ceftriaxone. Thus, the combination therapy of Pep19-2.5 and ceftriaxone holds promise as a candidate for human sepsis therapy. Combination therapy with a peptide that binds to and neutralizes toxins and the antibiotic ceftriaxone may treat bacterial sepsis in humans. Bacterial sepsis is a complex reaction to bacteria and their toxins, and is a major cause of death worldwide. Klaus Brandenburg and colleagues at the Leibniz-Center for Medicine and Biosciences in Germany, with co-workers in Spain, Germany and Japan, tested the potential of the combination therapy in rabbits. They suggest rabbits may be a better model for sepsis than the more commonly used mice, as treatments successful in mice often fail in human clinical trials. The intravenous combination therapy killed bacteria, reduced several biochemical indicators of sepsis and restored normal body temperature. The therapy may avoid many of the problems and limitations of existing approaches for treating sepsis.